Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-sp ecific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha ) were given to 17 adult patients with severe falciparum malaria immediatel y before treatment with artesunate in a pilot study to assess safety and op timal dosage with a view to future studies. Clinical and laboratory variabl es were compared with II controls. In the groups given Fab, there was a ten dency for a faster resolution of clinical manifestations and reduction of f ever but also a tendency towards longer parasite clearance times. Adverse e vents were more common in the control group and no early anaphylactic or la te serum sickness reactions occurred in the Fab treated patients. On admiss ion all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interfero n-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increase d IL-8 levels, and 21% had increased IL-1 beta levels. Antibody treatment r educed IFN-gamma concentrations in a dose-related manner, but had no obviou s effects on levels of other cytokines in this small study, although unboun d TNF-alpha was undetectable after Fab treatment. Circulating concentration s of soluble E-selectin, intercellular adhesion molecule-1 and vascular cel l adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.